Ketoaliphatic acids derived from hydroxy and alkoxy diphenyl alkanes and the production thereof



Patented Mar. 1 1,, 1 952 KETOALIPHATIC ACIDS DERIVED FROM HY- DROXY ANDALKOXY DIPHENYL ALKANES AND THE PRODUCTION THEREOF Robert R. Burtner,Skokie, Ill., and Harry A. Arbit, Los Angeles, Calif.,. assignors to: G.D.

Searle &' 60., Chicago,

Illinois 111., a corporation of No Drawing; Application April 10, 1950,Serial No. 155,126

13- Claims. (CL- 260520) This invention relates to substituted phenyalkylbenzoylaliphatic acids, to salts thereof, and to methods for theproduction of such compounds. In particular this invention relates tocompounds of the general structural formula wherein A and B are bivalentaliphatic hydrocarbon radicals, E and F are members of. the classconsisting of hydrogen, halogen, hydroxyl, lower alkyl and alkoxylradicals, D is a member of the class consisting of hydrogen, halogen,hydroxyl, lower alkoxyl and radicals of. the type or branched chainarrangement such as methylene, ethylene, propylene, butylene, pentylene,hexylene, heptylene, octylene and polymethylene from trimethylene tooctamethylene. Unsaturated aliphatic hydrocarbon radicals containing oneor two double bonds, such as vinylene and allylene, are likewise withinthe scope of this invention. B is a member of the same class of bivalentaliphatic hydrocarbonradicals, excluding only methylene. R representshydrogen or a lower alkyl radical such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, secondary-butyl, tertiary-butyl and thelike. D, E' and F represent hydrogen, fluorine, chlorine, bromine,iodine, hydroxyl, alkyl groups of the foregoing. type. and correspondinglower alkoxyl groups. X represents one. equivalent of a-cationsuch ashydrogen, an alkali metal ion, an, alkaline earth metal. ion, an;ammonium ion. and an amine ion. The object of. this invention. is to.provide novel chemical substancesfl of the type indicated; above and to.provide simplev and economical. methods of, producing such substances,Further it. is. the object of the invention to providefeasible syntheticmethods for the manufacture. of the foregoing substances from. readilyavailable starting materials. In certain instances, it was foundnecessary to provide improved methods for obtaining such startingmaterials. For example, in. the case of. 2,.4-dimethoxydiphenylmethane,the methods given in the literature are: not satisfactory (cf. Skraupand Bohm, Ber. d. Deut. Chem. Ges. 59, 1011; 1926; and Klarmann, J. Am.Chem. Soc. 48, 792; 1926). We have discovered that this compound may beobtained by condensing at an elevated temperature m-dimethoxybenzenewithbenzyl chloride, and that yields are particularly good inthepresence of a metallic catalyst, preferably copper or a copper compoundsuch as the oxide, sulfate, chloride and the like.

The compounds of the invention are useful as therapeutic agents and asintermediates in chemical synthesis. Thus, certain of them are efiectiveas chol'eretic agents. For this purpose, they may be administered in theform of the free acids or in the form of water soluble salts. Further,certain of these compounds are useful as parasiticidal agents. Certainof the compounds in which the bivalent aliphatic hydrocarbon radical,

referred toherein as A, is highly branched are useful in the preparationof steroid-like com poun'q.

The compounds of thisi'nvention are prepared by reacting aralkylphenylalkyl' etherswith a dibasic aliphatic acid anhyd'rid'eor halide derivedfrom a dibasic acid of the following formula HOOC-Be-COOH with aFried'el Crafts type catalyst, generally in an inert organic solvent.Among such catalysts are anhydrous. aluminum chloride, anhydrous ferricchloride, stannic chloride, boron trifiuori'de', zinc chloride, hydrogenfluoride, sodium-aluminum chloride and similar substances. The inertsolvents are organic liquids having chemicalreactivities'lower than thatofthe foregoing ethers and include nitrobenzene, carbon disulfide,chlorobenzene, tetrachloroethane; and relateddsubstances. Among thedibasic acid anhydridesgand halides which can be used in preparingthesecompounds are succinic, glutarlc, adipic,. pimelic, suberiasebacic,maleic, fumaric, methylsuccinic, ethyl. succinic, alpha-methylglutaric,beta-methyIgl-utaricg alpha-methyladi'pic and related di' in which X isa halogen, preferably chlorine, are likewise useful in the preparationof such compounds.

The alkoxyl compounds obtained in the Friedel-Crafts reaction may bedealkylated to form the free hydroxyl derivatives by the usual methodssuch as by use of aluminum chloride or such hydrohalic acids ashydrobromic or hydriodic acid.

Salts of the keto acids which comprise this invention can be prepared bytreatment of an alcoholic solution of the free keto acid with analcoholic solution of an alkali, and subsequent evaporation orprecipitation with a solvent in which the salt is insoluble, as forexample, ether, benzene, acetone, and the like. Salts can be prepared ofthe alkali metals as well as watersoluble aliphatic or aliphatic-typebases, such as the lower mono-, di-, and trialkylamines, alkanolamines,and aliphatic-type cyclic amines such as morpholine. The salts aresoluble in water and have the same properties as the free acids. Theytherefore constitute a preferred form of the compounds of thisinvention.

' Our invention will be described more fully in conjunction with thefollowing examples. It should be understood, however, that'theseexamples are" given by way of illustration only and theinvention is notto be construed as limited in spirit or in scope by the details setforth. It

will be apparent to those skilled in the art that many modifications inmaterials and methods may be made without departing from the invention.In each of these examples, temperatures are given in degrees centigrade,relative amounts of materials are given in parts by weight, andpressures during vacuum distillation are measured in millimeters" (mm)of mercury.

- EXAMPLE-1- Beta- ('3 -benzyl-4-methoxybcnz'oyl)' propzom'c acid To anagitated suspension of 396 parts of o-benzylanisole and 200 parts ofsuccinic anhydride in 2400 parts of nitrobenzene at to C. -areadded over30- minutes 536-parts of anhydrous aluminum chloride with goodagitation. The mixture is stirred for 2 hours jpnger at about 0 C. andthen allowed to stand for hours. The mixture is decomposed with ice andacid'and steam distilled to remove solvent. The residue ischilled andthe granular precipitate is removed and dissolved in 8000 parts of 2%sodium hydroxide solution. This alkaline solution is agitated withactivated charcoal, filtered, and acidified. The precipitate of beta-(3-benzyl-4-methoxybenzoyl) -propionic acid is separated and dried. Afterrecrystallization from methanol, it melts at about 133 C.

I 4 EXAMPLE 2 Beta- (-3-benzyl-4-hydroa:ybenzoyl) propzom'c v acid v Asuspension of 10 parts of beta-(3-benzyl4- methoxybenzoyhpropionic acidin 120 parts of hydriodic acid (specific gravity 1.7) and 'parts ofacetic anhydride is refluxed for 15 minutes during which time the aciddissolves. The resulting solution is poured into 200 parts of ice water.The precipitate "of beta-"'(3-benzyl-4- 4 hydroxybenzoyhpropionic acidis separated, washed and dried. It melts at about 185.5 C. afterrecrystallization from ethyl acetate.

EXAMPLE 3 Beta- 3-benzyZ-4-methoa:ybenzoyl)acrylic acid at 0 to 3 C. Themixturcis agitated for 2 hours more at ice temperature and then allowedto stand for 15 hours slowly coming to room temperature during thistime. The mixture is decomposed with ice and acid and steam distilled toremove solvent. The organic residue is dis- 1 solved in 8000 parts of 2%carbonate solution at room temperature. It is treated with activatedcharcoal at room temperature and filtered. The filtrate is acidified andthe granular precipitate of beta-(3-benzyl-d-methoxybenzoyl) acrylicacid is separated, washed with water, dried, and recrystallized fromethyl ,acetate using decolorizing charcoal. It forms yellow needlesmelting at about 156 C.

EXAMPLE 4 Beta- (Z-methomy-S -benzylbenzoylapropionic acid EXAMPLE 5Beta -(2-hydr0xy-5-benzylbenzoyl) propionic acid A suspension of 15parts of beta-(2-methoxy- 5-benzylbenzoyl)propionic acid in 135 parts of47% hydriodic acid and 32.5 parts of acetic anhydride is refluxed for 35minutes. The mixture is then diluted with ice water and the oily acidallowed to granulate. The precipitate is collected on a filter,triturated with water and dried. Recrystallization from ethyl acetateyields colorless crystals of pure beta-(2-hydroxy-5-benzyl)propionicacid, which melts at about 161 C. With ferric chloride an amethyst coloris obtained."

EXAMPLE 6 2,4-dimethoxydiphenylmethane ane which distils at to C. atthat pres sure. The n is 1.5764.- The' distillation residue. consistsmainly of ZA-dimethoxy-S-benzyl diphenylmethane, which oncrystallization from ethanol-melts at 98 C.

5 EXAMPLE: 7'

Beta- (2;4-aimethoxy 5-benzylbeneoyl')propionic,

208 parts of' 2,4-dimethoxydiphenylmethane in 5 the presence of 244'parts of anhydrous aluminum chloride in 1260 parts: of nitrobenzene at(1 to-5 according to the method of Example. 1. The mixture is stirredfor 20 minutes longer at (1 C., allowed to stand for hours, and isquenched with iceand acid. The solvent isremoved. by" steam distillationand the residue is taken up in 10.,000 parts of 2% sodium carbonatesolution at 90 C. The solution is chilled and extracted with. ether. Itis then acidified and an oily precipitate of beta-(2,4-dimethoxy-5-benzylbenzoyl)propionic acid soon granulates. This iswashed with water, dried, and crystallized from methanol usingdecolorizing charcoal. The acid so obtained melts at about 177 C.

EXAMPLE 8 Beta- [p- Z-methcxy-5-chlorobenzyh' benzoyl] propz'omc acid580' parts of 2'-benzyl-l-chloroanisole and 250 parts of succinicanhydride suspended in 3000 parts of nitrobenzene are reacted at 0 to 3C'. with 670 parts of anhydrous aluminum chloride, good agitation beingmaintained throughout the reaction. Stirring is continued for 6 hours at0 C. and the mixture is then allowed to stand at room temperature for 15hours.

EXAMPLE 9 Beta- [p- (2-hyaroxy-5-chlorobenzyl) benzoyll propionic acid 7The acid described in Example 8 is demethylated by the method given inExample 2. The crude product is crystallized from acetic acid usingcharcoal as a decolorizing agent. The colorless crystals cf the pureacidmelt at about 200 .to 201 C. with decomposition.

EXAMPLE" 10 Beta- [-10- (Z-methoxy-5-chlorobeneyl) benzoyll acrylic acid58 parts of 2-benzyl-4-chloroanisole and 245 parts of maleic anhydridesuspended in 3000' parts of nitrobenzene are reacted with good agitationwith 670 parts of aluminum chloride added portionwise. The mixture ismaintained at 0 C. during the addition and for 2 hours longer, efficientagitation being maintained throughout. The reaction mixture is allowedto stand for hours at room temperature and is then quenched with dilutehydrochloric acid and ice. The acid is steam distilled to remove solventand the aqueous residue chilled. The beta-[p-(Z-methoxy-5-chlorobenzyl)benzoyllacrylic acid is dissolved in a cold solution ofaqueous alkali which is then Washed with ether. To remove all traces ofether,. the alkaline solution is aerated. Heating 0 to 148 C.

is: to be. avoided to prevent. decomposition. Aciditfication. produces abrown amorphous precipitate; On crystallization from methanol and thenfrom: benzene the pure, acid. is obtained which melts at about 162" C.

EXAMPLE 11 Beta- [3- (o-methoxyphenethyl) 4-methoxybenzoyllpropz'om'cacid and 2,2-dimethoxy-5,5'-bis- (beta-carbomypropionyl) bibenzyl To anagitated: suspension of 538 parts of 2,2- dimethoxydiphenylethane and220 parts of succi'nic anhydride in 2650 partsof nitrobenzene at 0 to 5C. are added in the course of minutes 590 parts of anhydrous aluminumchloride with rinsed and dried. The mixture is extracted exhaustivelywith hot methanol and the hot extracts clarified' with charcoal. Themethanol solution is concentrated and treated with a large volume ofWarm water. The dark granularprecipitate is recrystallized first frombenzene and then from ethyl acetate, with the use of charcoal as adecolorizing agent. The colorless beta- [3-(0- methoxyphenethyl) 4methoxybenzoyllpropicnic-acid melts at about 141 to 142 C.

The; methanol insoluble fraction is dried and the gray powder is:converted by crystallization from acetic acid and decolorization. withcharcoal into minute nearly colorless crystals which melt at 250 C. withdecomposition. This fraction has the following structure eon; omoQCHz-CHE -.o omomooon ooon'zomo 0 on EXAMPLE." 12

Beta- [3% o hgdroaIgphe nethyZ) -4-hydroa:y-

benzoyllpropionic acid" The beta-[3(o-methoxyphenethyll-4-methoxybenzoyll-propionic acid is demethylated bythe method described in Example 2'. The crude acid is leached withboiling benzene to remove impurities. The pure crystals melt at about147 EXAMP E 1 3.

Omega- [3- (:p-cymenyl) -4-methomybenzoyl] valeric acid To an agitatedsuspension of 480 parts of o-(p-cumyl) anisol'e and 256' parts of adipic anhydride in Sou-parts of nitrobenzene and 3200" parts oftetrachloroethane at 0 to 5 C. are added over 30--minutes 267 parts ofanhydrous aluminum chloride; The mixture is stirred for three hours 7longer at 0 to 5 C; and then allowed to stand removed and dissolved in alarge volume of- 2% sodium hydroxide solution. This solution is a itatedwith activated charcoal, filtered and acidified. The precipitatedomega-[B-(p-cymenyl) 4-methoxybenzoyllvaleric acid is separated, washedwith water and dried. Upon recrystallization from methanol, it formscolorless needles, which are moderately soluble in dilute alkali.

EXAMPLE 14 Beta- [2 -methyl-4-methoa:y-5- (beta-phenylpropyl)benzoyllpropionic acid 91 parts of succinic anhydride are reacted with234 parts of Z-(beta-phenylpropyl) --methylanisole in the presence of244 parts of anhydrous aluminum chloride in 1300 parts of nitrobenzeneat 0 to 3 C. with vigorous agitation. After completion of the additionthe mixture is stirred forZ hours longer at 0 to 3 C., allowed to standfor hours, and quenched with ice and acid. The solvent is removed bysteam distillation and the residue worked up as in example 13.Recrystallization of the beta-[2-methyl-4-methoxy-5-(beta-phenylpropyl)benzoyllpropionic acid from methanol yields colorlessneedles, which are moderately soluble in dilute alkali.

EXAMPLE 15 3- (4' -metho:cyphenyl) -4- (3 -betacarbozcypropionyl-4'-methoa:yphenyt) hexane A solution of parts of3,4-bis-(p-methoxyphenyl)hexane (meso form, melting point 140 to 142 C.)and 7 parts of succinic anhydride in 120 parts of nitrobenzene is cooledto 4 C. Then 21.3 parts of anhydrous aluminum chloride are added insmall portions to the agitated solution, the temperature beingmaintained at 4 to 5 C. After the addition, the mixture is allowed tostand for about 15 hours. The reaction mixture is then poured into 200parts of ice containing parts of concentrated hydrochloric acid, and thenitrobenzene is removed by steam distillation. The residue is chilled,and the brown solid is separated and washed twice by decantation. It isthen heated with a solution of 35. parts of sodium carbonate in 300parts of water. The alkaline extract is treated with decolorizingcharcoal and filtered. The filtrate is added slowly with stirring to anexcess of 10% hydrochloric acid. The light-colored granular precipitateof the 3- (4-methoxyphenyl) -4-( 3-beta-carboxypropionyli-methoxyphenyl) hexane is collected on a filter,washed with water and dried.

This compound has the formula OCH;

EXAMPLE 16 3- (4'-hydro:ryphenyl) -4- (3-beta-carboa1ypropionyZ-4'-hydro:ryphenyl) hexane phenyl) 4 -(3'- beta-carboxypropionyl 4'-hydroxyphenyhhexane which melts at about to C. EXAMPLE 1'?3-(4-met'ho:ryphenyl) -4- (3'-betc-carboa:ypropionyZ-4 methoxyphenyl)hexane 30 parts of 3,4-bis-(p-methoxyphenyl) hexane (racemic form,melting at 52 to 54 C.) and 10 parts of succinic anhydride in 150 partsof nitrobenzene are treated with 29.3 parts of aluminum chloride as inExample 15 and this form of3(4'-methoxyphenyl)-4-(3-beta-carboxypropionyll'-methoxyphenyl)hexane isisolated by the procedure of Example 15.

EXAMPLE 18 3-(4'-hydroa:yphenyl) 4 (3-beta-carboxypropionyl-4-hydro:z:yphenyl) hexane 31 parts of the acid described in Example 17are refluxed for 2 hours with a solution of 215 parts of hydriodic acid(specific gravity 1.7) in parts of glacial acetic acid and 100 parts ofacetic anhydride. The purified low-melting form of the3-(4'-hydroxyphenyl) -4- (3-beta-carboxypropionyll'-methoxyphenyl)hexaneis isolated by the method of Example 16 and melts at about 55 to 65 C.

EXAMPLE 19 2-(4'-methoxyphenyl)-3 (3-beta-carbo:rypropionyZ-4'-methozcyphenyl) butane.

This compound is obtained by the process described in Example 15 using27 parts of 2,3-bis- (F-methoxyphenyDbutane, 10 parts of succinicanhydride and 30 parts of anhydrous aluminum chloride in parts ofnitrobenzene.

EXAMPLE 20 .2-(4'-hydro;ryphenyl) 3(3'-beta-carbozrypropionyl-4'-hydromyphenyl) butane.

The product of Example 19 is demethylated by the procedure described inExample 16 using parts of hydriodic acid (specific gravity 1.7) in amixture of glacial acetic acid and acetic anhydride.

EXAMPLE 21 3 -(4-methoa:yp henyl) 4 -(3-delta-carboxyvaleryl- 4-methomyphenyl) hexane.

To a solution of .15 parts of 3,4-bis-(p-methoxyphenyDhexane and 7.5parts of adipic anhydride in 100 parts of nitrobenzene at 4 C. are addedportionwise with good agitation 16 parts of anhydrous aluminum chloride.After standing overnight, the mixture is quenched in ice containing 25parts of 20% muriatic acid. The solvent is removed by steam distillationand the residue is chilled. The precipitate of crude keto acid isremoved and dissolved in dilute sodium carbonate solution. This istreated with decolorizing charcoal, filtered and added slowly to anexcess of dilute mineral acid. The acid obtained has the structuralformula on,oC -on-cn -oorn 321 5 (BIHA O"(CHI)"COOH EXAMPLE 223-(4'-hydro:cyphenyl) 4 (3'-delta-carboxyvalowl-4 -hydroacyphenyl)hexane.

The aciddescribed in Example 21 is 'demethylated by heating with 150parts of hydriodic acid acetic anhydride for 40 minutes.

no 10H GomornG-o OCHzCHzCHzCHg-C on and 3,3'-dihydroxy-6-deltacarboxyvalerylbibenzyl of the formula- These compounds are prepared from3,3'-dimethoxybibenzyl by the methods of Examples 11 and 12.

B. 3-(p-hydroxyphenyl) (p-hydroxy mbeta-carboxypropionylphenyl)-4-ethylheptane C O-GHrCHa-C O OH This substance is produced from3,5di-(p-methoxyphenyl) -4-ethylheptane and succinic anhydride accordingto the processes of Example 15.

EXAMPLE 24 2,2',4,4'-tetrametho:ry-5,5 bis (beta-carbomypropionyl)biphenyl 1125 parts of anhydrous aluminum chloride are added portionwiseat 0 to 3 C. to an agitated suspension of 548 parts of2,2',4,4'-tetramethoxybiphenyl and 420 parts of succinic anhydride in4800 parts of nitrobenzene. Stirring is continued for 2 additional hourat 0 and the mixture is r then allowed to stand at room temperature forhours. Hydrolysis, steam distillation of the solvent and work-up in theusual manner through alkaline extraction produces a mixture of crudeacids due to partial cleavage of one or more of the methoxy] groups.Remethylation with an excess of dimethyl sulfate in potassium hydroxidesolution yields a 2,2,4,4-tetramethoxy-5,5'-bis-(beta-carboxyp-ropionyl)biphenyl which shows only a faint ferricchloride test. Two successive crystallizations from acetic acid usingcharcoal as a clarifying agent yield the pure acid in crystals whichmelt at about 232 C.

EXAMPLE 25 2,2-dimetho:ry-4,4'-dihydro:cy-5,5'-bis-(betacarbomymopionyl)-biphenyl A suspension of 18 parts of the 2,2',4,4'-tetramethoxy 5, 5bis (beta carboxypropionyl) biphenyl, described in Example 24, isrefluxed in 540 parts of 47% hydriodic acid and 157 parts of Themicrocrystalline suspension is diluted with ice water, collected on afilter and rinsed to obtain pale yellow crystals which are insoluble incommon orboiling acetic acid leaves nearly rcolorless,t2,2'-

dimethoxy 4,4 dihydroxy-5,5'-bis-(beta carboxy-propionyhbiphenyl; whichmelts-at about 315 C. with decomposition. A very dilute suspension inethanol gives a muddy brown color with ferric chloride.

We claim:

1. A compound of the structural formula wherein A is a lower bivalentaliphatic hydrocarbon radical containing one to eight carbonatoms,,inclusive,; B is a lower bivalent aliphatic hydrocarbon radicalcontaining two to eight carbon atoms, inclusive, E and F arememb'ers ofthe class consisting of hydrogen, halogen, lower alkyl, hydroxyland'lower alkoxyl radicals, D -is a member of the class consisting of'hydrogenjhaldgen, hydroxyl, lower 'alkoxyl radicals and radicals of theformula COBCOOX, R. is amem'ber of the class consisting of hydrogen andlower alkyl radicals, and X is a member of the group consisting ofhydrogen and one equivalent of a cation.

2. A compound of the structural formula wherein A is a lower bivalentaliphatic hydrocarbon radical containing one to eight carbon atoms,inclusive, B is a lower bivalent aliphatic hydrocarbon radicalcontaining two to eight carbon atoms, inclusive, E is a lower alkoxylradical and R is a lower alkyl radical.

3. A compound of the structural formula 0 CH3) n Wag wherein n is aninteger smaller than 3.

6. A beta-(benzyldimethoxybenzoyl) propionic acid.

'7. A compound of the structural formula CH O 8. A compound of thestructural formula COBCOOH wherein B is a lower bivalent aliphatichydrocarbon radical containing two to eight carbon atoms; inclusive, andn is an integer smaller than 3.

9. A compound of the structural formula wherein n is an integer smallerthan 3.

10. A beta-(benzyldihydroxybenzoyl) propionic acid.

11. A compound of the structural formula.

12. A compound of the structural formula wherein R is a lower alkylradical and n is an integer smaller than 3.

13. A compound of the structural formula OCHI n 43 o 0-0 H=C 11-0 0 0Hwherein n is an integer smaller than 3.

ROBERT R. BURTNER.

HARRY A. ARBIT.

REFERENCES CITED The following references are of record in the file ofthis patent:

Fieser et al.: Chem. Abs., vol. 30, p. 7565 (1936). Trivedi et al.:Chem. Abs., vol. 36, col. 3801 Nicholas et al.: J. Chem. 800., vol.1949, p. 257.

1. A COMPOUND OF THE STRUCTURAL FORMULA